ABSTRACT
BACKGROUND/AIM: Oxidative stress is involved in several carcinogenic pathways. Nuclear factor erythroid 2-related factor (Nrf2), Kelch-like ECH-associated protein 1 (Keap1) and Park7 (DJ-1) are the main regulators of antioxidant enzymes eliminating reactive oxidative species (ROS). The roles of these proteins were studied as potential prognostic factors in endometrial cancer. MATERIALS AND METHODS: Nrf2, Keap1 and DJ-1 expression in endometrial carcinomas was analyzed immunohistochemically. Correlations between staining patterns and clinical prognostic variables were evaluated. RESULTS: Extensive cytoplasmic Keap1 staining correlated to several factors associated with poor prognosis of endometrial cancer including advanced stage, poor histological differentiation, lymphovascular invasion, pelvic lymph node metastasis and deep myometrial invasion. In multivariate analysis, cytoplasmic Keap1 was a stronger predictor of poor progression-free survival than grade. Nuclear Nrf2 staining was seen in all patients with lymph node metastasis while DJ-1 staining was associated with clinically favourable disease types. CONCLUSION: Cytoplasmic Keap1 expression indicates poor prognosis in endometrial cancer.
Subject(s)
Cytoplasm/metabolism , Endometrial Neoplasms/diagnosis , Endometrial Neoplasms/metabolism , Kelch-Like ECH-Associated Protein 1/metabolism , Aged , Aged, 80 and over , Antioxidants/metabolism , Carcinoma/diagnosis , Carcinoma/metabolism , Carcinoma/mortality , Cell Differentiation , Cell Nucleus/metabolism , Decision Making , Disease-Free Survival , Endometrial Neoplasms/mortality , Female , Humans , Immunohistochemistry , Kaplan-Meier Estimate , Middle Aged , Multivariate Analysis , Myometrium/metabolism , NF-E2-Related Factor 2/metabolism , Oxidative Stress , Prognosis , Protein Deglycase DJ-1/metabolism , Reactive Oxygen Species/metabolismABSTRACT
To determine the mechanisms underlying the changes in collagen metabolism responsible for muscle fibrosis in patients with neuromuscular diseases, the synthesis and degradation of collagens was studied in muscles of patients with polyneuropathy and noninflammatory myopathies. The mRNA levels for type I, III, and IV collagens and immunohistochemical staining intensities for collagen propeptides and telopeptides were increased in polyneuropathy, suggesting enhanced synthesis of collagens. In myopathy, the mRNA levels were at the control level. Matrix metalloproteinase (MMP)-2 mRNA level was increased in polyneuropathy, although the quantity of proMMP-2 was not changed. An increase in type IV collagen concentration and proMMP-9 expression was observed in polyneuropathy but not in myopathies. Our results suggest that intramuscular accumulation of type IV collagen occurs in polyneuropathy, possibly leading to thickening of the capillary and muscle fiber basement membranes. This may complicate the transportation of nutrients and cellular excreta between blood and muscle cells.
Subject(s)
Collagen/biosynthesis , Collagen/metabolism , Neuromuscular Diseases/metabolism , Polyneuropathies/metabolism , Adolescent , Adult , Aged , Collagen/genetics , Collagen Type IV/metabolism , Female , Humans , Immunohistochemistry , Male , Matrix Metalloproteinase 2/metabolism , Matrix Metalloproteinase 9/metabolism , Middle Aged , Neuromuscular Diseases/enzymology , Neuromuscular Diseases/genetics , Polyneuropathies/genetics , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Statistics, NonparametricABSTRACT
Acute downhill running has been shown to activate matrix metalloproteinase- (MMP-) 2 and to change type IV collagen concentration in some muscle types. In order to study the influence of more intense exercise on total collagen and type IV collagen concentrations, molecules regulating their synthesis and degradation were investigated after forced lengthening contractions in rat skeletal muscle. Tibialis anterior (TA) muscle of 24 male Wistar rats was subjected to 240 forced lengthening contractions. TA muscle was excised at consecutive time points (0 and 6 h, 2, 4, and 7 days) after stimulation. With immunohistochemistry, types I, III and IV collagen were located in the swollen, necrotic and regenerated fibres in a similar manner as in intact undamaged skeletal muscle fibre. An increase in the activity of prolyl 4-hydroxylase was indicative of an overall elevated collagen biosynthesis. No change was demonstrated in total collagen concentration, whereas type IV collagen concentration increased after exercise. MMP-2 and MMP-9, which are the proteins that degrade type IV collagen, elevated after exercise. In conclusion, the increase in type IV collagen concentration seems to be the result of an increase in both the synthesis and activation of degrading enzymes and their inhibitors during recovery after forced lengthening contractions.
